The phosphodiesterase enzymes play an integral role in cell signaling mechanisms by hydrolyzing cAMP and cGMP to their inactive 5′ forms. Inhibition of PDE enzymes results in an elevation of cAMP and/or cGMP levels and alters intracellular responses to extracellular signals by affecting the processes mediated by cyclic nucleotides. It has been demonstrated that increasing cAMP levels within these cells results in suppression of cell activation, which in turn inhibits the production and release of pro-inflammatory cytokines such as TNF-α. Since eosinophils are believed to be a critical pro-inflammatory target for asthma, identification of the expression of the PDE4 gene family in eosinophils led to PDE4 as a potential therapeutic target for asthma [Rogers, D. F., Giembycz, M. A., Trends Pharmacol. Sci., 19, 160-164, (1998); Barnes, P. J., Trends Pharmacol. Sci., 19, 415-423, (1998)].
PCT Publication No. WO 2006/064355 (WO '355) discloses PDE4 inhibitors of the formula
including, 3,5-dichloro-4-(6-difluoromethoxybenzo[4,5]furo[3,2-c]pyridin-9-ylcarboxamido)-1-pyridiniumolate. 6-(difluoromethoxy)[1]benzofuro[3,2-c]pyridine-9-carbaldehyde, is an intermediate useful for preparing compounds with PDE4 inhibitory activity such as 3,5-dichloro-4-(6-difluoromethoxy benzo[4,5]furo[3,2-c]pyridin-9-ylcarboxamido)-1-pyridiniumolate.
WO '355 discloses processes for preparing these compounds. However, these processes are not suitable for commercial scale production of the compounds as they require hazardous reagents (such as 4-methylbenzenethiol, tin(IV)chloride and dichloromethylmethyl ether), have low yield, and produce the compounds in low purity.
The present invention provides alternative novel processes, which is economical, convenient, efficient and easily scalable. Furthermore, the yields and purity of intermediates, including 6-(difluoromethoxy)[1]benzofuro[3,2-c]pyri dine-9-carbaldehyde, and final products are high.